DOI: 10.1002/chem.201503284
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& C¢H Activation
Palladium(II)-Catalyzed Acetoxime Directed ortho-Arylation of Aromatic Alcohols Kun Guo,[a] Xiaolan Chen,[a] Jingyu Zhang,[b] and Yingsheng Zhao*[a] Abstract: Biaryls, which contained a benzyloxy motif, were directly constructed through a ligand-promoted PdII-catalyzed ortho-arylation of masked aromatic alcohols. A variety of acetoxime ethers could be coupled with a diverse range of arylboronic acid pinocol esters, giving direct access to
Introduction Development of controlling site-specific functionalization of C¢H bonds offers an innovative approach to construct the core structures of pharmaceutical agents, natural products, and organic materials.[1] Harnessing a directing group to enable site-selective C¢H functionalization is one of the most successful strategies;[2] however, such transformations are sometimes in conflict with the directing groups available in a particular starting material. Despite great efforts that have been made in the last few decades to exploit varieties of auxiliaries for amines,[3] acids,[4] and ketones[5] in transition-metalcatalyzed direct C¢H functionalization, it remains a significant challenge to develop alcohol or masked alcohol-directed C¢H oxidation and C¢C formation reactions,[6] due to the possible oxidation of the hydroxyl group, weak coordination of alcohols with PdII, and the constraints of introducing suitable surrogate groups for alcohols. In 2010, breakthroughs were achieved by Yu and co-workers, who made a series of reports on PdII-catalyzed hydroxy-directed ortho-olefination,[7] intramolecular cyclization,[8] and carbonylation[9] of phenethyl alcohols. However, the use of secondaryor primary alcohols afforded lower yields. Meanwhile, Hartwig and co-workers developed a practical hydroxyl-directed orthosilylation of benzyl alcohols by employing an Ir catalyst, followed by a separate Hiyama-type coupling of the benzoxasiloles with aryl halides.[10] Despite these advances, there is still
bioactive biaryls in modest to good yield. Not only could acetoxime be subsequently removed without a separation, functionalized hydroxylamine derivatives could also be obtained.
a demand to more efficiently and directly construct biaryls containing a benzyloxy motif, which are the omnipresent component of many drug candidates, for example, in known HNF4a modulators,[11] JTT-305,[12] and VEGF receptor inhibitors[13] (Figure 1; HNF = hepatocyte nuclear factor, VEGF = vascular en-
Figure 1. Biologically active compounds containing a benzyloxy motif.
dothelial growth factor). Recently, our group reported acetoxime directed ortho-olefination of masked aromatic alcohols through a six- or seven-membered exo-palladacycle (Scheme 1 A).[14] Though the crystallization of exo-palladacycle intermediate demonstrated the ability of exo-directing mode, we have not tapped its potential. Herein, we report the first PdII-catalyzed cross-coupling of O-benzylacetoximes with arylboron reagents, in which oxime serves as an exo-type directing
[a] K. Guo, X. Chen, Prof. Dr. Y. Zhao Key Laboratory of Organic Synthesis, Jiangsu Province College of Chemistry Chemical Engineering and Materials Science, Soochow University Suzhou 215123 (P. R. China) E-mail: [email protected] [b] Dr. J. Zhang College of Physics Optoelectronics and Energy & Collaborative Innovation Center Suzhou Nano Science and Technology, Soochow University Suzhou 215006 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201503284. Chem. Eur. J. 2015, 21, 17474 – 17478
Scheme 1. PdII-catalyzed acetoxime-assisted C¢H functionalization. NHPI = Nhydroxyphthalimide, DEAD = diethyl azodicarboxylate.
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Full Paper group, and can be subsequently removed without a separation (Scheme 1 B). While oxime is well-known for transition-metal-catalyzed C¢H activation of masked ketones,[5, 15] Dong and co-workers developed the first exo-oxime-directed acetoxylation of masked alcohols under PdII/PdIV catalysis.[16] In this seminal report, they developed a catalytic alcohol b-C(sp3)¢H activation and C¢O formation reaction, where using a 2,6-dimethoxylbenzaldoxime as novel bidentate directing group was found to be crucial.[16a] Later, they expanded its application in Pd-catalyzed ortho-acetoxylation of masked benzyl alcohol.[16b] However, we envisioned that using concise acetoxime as monodentate directing group should also be beneficial to the arene C¢H activation, because 1) O-benzylacetoximes are simple and readily available, which can be easily synthesized from an SN2 reaction of benzyl halides with acetone oxime,[17] or prepared from widely available alcohols though a one-pot procedure (Scheme 1); 2) the acidic a-hydrogens in acetoxime are rather stable under mild oxidative conditions;[14] 3) tuning the reactivity and selectivity of catalysts can be achieved through the use of external ligands;[18] 4) not only is acetoxime used as a traceless directing group, but hydroxylamine[13, 19] also exists in bioactive molecules.
Table 1. Optimization of reaction conditions.[a]
Results and Discussion Initially, we treated acetoxime ether 1 a with phenylboronic acid pinacol ester 2 a at 120 8C for 10 h with a combination of different oxidants, bases, and ligands (Table 1). Preliminary results revealed that the use of Pd(TFA)2 (10 mol %), Ac-Gly-OH (10 mol %), and Ag2CO3 (2 equiv) in t-amylOH (0.5 mL) gave the ortho-arylation product 3 a in 85 % yield (Table 1, entry 1). In a further investigation into the performance of different bases, no positive effect was observed in the presence of common weak bases (entries 2–8). Interestingly, the addition of KBF4 facilitated this transformation, giving 3 a in 93 % yield (entry 9). Although the reason needs to be further explored, we speculated that the KBF4 would play the role of a pH buffer in the catalytic cycle, which would stabilize the palladium intermediate. Among the palladium catalysts screened, though Pd(OAc)2, Pd(PPh3)Cl2, Pd(CH3CN)2Cl2, and PdCl2 resulted in moderate to good yield (entries 10–13), Pd(TFA)2 was found to be superior. Because of competitive PdII-mediated protonation and homocoupling of the arylboron reagents, the use of 10 mol % of catalyst was deemed necessary (entries 9 and 14). Having identified the best catalyst, we proceeded to evaluate the optimal oxidant. The oxidants such as AgOAc, Ag2O, Cu(OAc)2, and 1,4-benzoquinone (BQ) were all tested (entries 15–18); however, Ag2CO3 still turned out to be the best. From previous studies, the ligands can adjust the steric and electronic properties of coordinated PdII centre.[18d,e,g, 20] Thus, the ligand of Ac-Gly-OH, which could significantly promote C(sp2)¢H activation and subsequent coupling reactions, was indispensable (entries 9 and 19). In the absence of a palladium catalyst, the control experiment gave no product (entry 20). With optimized conditions for the cross-coupling in hand, various masked aromatic alcohols were prepared and examChem. Eur. J. 2015, 21, 17474 – 17478
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Entry
Catalyst
Oxidant
Base
Yield[b] [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14[c] 15 16 17 18 19[e] 20
Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(OAc)2 Pd(PPh3)Cl2 Pd(CH3CN)2Cl2 PdCl2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 -
Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2O AgOAc[d] Cu(OAc)2 BQ Ag2CO3 Ag2CO3
– K3PO4 K2HPO4 KH2PO4 NaHCO3 Na2CO3 Li2CO3 NaBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4
85 5 31 83 49 38 87 84 93 51 77 80 77 84 18 39 12 3 8 0
[a] Reaction conditions: 1 a (0.2 mmol), 2 a (0.4 mmol), Pd catalyst (10 mol %), oxidant (2.0 equiv), base (2.0 equiv) in t-amylOH (0.5 mL), 120 8C, 10 h. [b] GC yield determined using tridecane as internal standard. [c] Pd(TFA)2 (5 mol %), Ac-Gly-OH (5 mol %). [d] AgOAc (4 equiv). [e] Without Ac-Gly-OH.
ined to test the generality of this methodology (Scheme 2). To our great delight, the electron-rich arenes provided the corresponding arylated products in moderate to good yield (3 c– g, i, j). In particular, both meta- and para-substituted benzyl alcohol derivatives afforded the corresponding mono-arylated products in good yield (64 %–83 %). Trace diarylated products were also observed in the reaction system (3 e–h). It is probable that the steric hindrance and coordinated effect inhibited the further arylation reaction. Furthermore, the a-substituted benzyl alcohols were all well-tolerated, affording arylated products in good to excellent yield (3 k–m, q). In particular, the acetoxime-protected 1,4-benzenedimethanol gave the mono-arylated product 3 o in a synthetically acceptable yield. Rather disappointingly, O-phenylacetoxime would be completely decomposed into undetectable smaller molecules under PdII/Pd0 catalysis (3 p). In contrast, the acetoxime-protected phenethyl alcohol afforded the arylated product in good yield with 2.5 equiv of 2 a, which may go through a rare seven-membered exo-palladacycle intermediate.[14] The efficiency of this acetoxime-assisted C¢H transformation encouraged us to evaluate the scope of arylboronic acid pinacol esters (Ar-BPins). In general, various para- and meta-substituted Ar-BPins were tolerated in this transformation, affording the corresponding products in good to excellent yield (Scheme 3). Gratifyingly, this synthetic protocol is compatible with various functional groups, including F, Cl, Ac, CF3, SO2Me,
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Scheme 2. C(sp2)¢H cross-coupling of Ar-BPin with various functionalized acetoxime ethers. [a] Reaction was carried out with 2 a (0.5 mmol).
NO2, Me, and OMe. Moreover, the 2-naphthylboronic acid pinacol ester gave the corresponding coupling product in good yield (4 g). Unfortunately, poor conversions were obtained for ortho-substituents on account of steric hindrance (4 n and 4 o). Similarly, heteroarylboronates that contained thianaphthene (4 p) and furan (4 q) were unreactive under this condition. To further demonstrate the synthetic simplicity and versatility of the acetoxime group, we developed a sequential procedure, which could accomplish arylation and removal of the directing group with one separation, to access arylated benzyl alcohols (Scheme 4). The key to make this protocol successful depends on the reduction of acetoxime by Raney Ni catalyst.[14] Alternatively, hydrolysis of acetoxime could obtain hydroxylamine derivatives.[21] Based on the above results and pioneering studies,[3f,g,h, 5a, 16, 18d, 22] the mechanism of acetoxime-directed orthoarylation reaction is proposed as depicted in Scheme 5.To begin with, the PdII species A, which is bound by amino acid ligand, coordinates with the substrate 1 and subsequently activates the ortho-C¢H bond, forming a six-membered exo-palladacycle intermediate B.[14] Transmetalation with Ar-BPin 2 produces intermediate C,[18d, 3h] followed by reductive elimination, Chem. Eur. J. 2015, 21, 17474 – 17478
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Scheme 3. C(sp2)¢H cross-coupling of acetoxime ethers with different ArBPins. [a] Reaction was carried out with 2 (0.5 mmol).
Scheme 4. Sequential arylation and removal of directing group.
releases the target molecule 3, with concomitant generation of Pd0 species D. Reoxidation with 2 equiv of AgI regenerates the active PdII species A for another catalytic cycle.
Conclusion We have developed the first example of acetoxime-directed ortho-arylation of masked aromatic alcohol derivatives via the
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Full Paper Natural Science Foundation of China (No. 21402133), and PAPD for financial support. Keywords: alcohols · arylation · C¢H activation · crosscoupling · synthetic methods
Scheme 5. Proposed catalytic cycle.
possible six- and seven-membered exo-palladacycle intermediate. A variety of acetoxime ethers can be coupled with a diverse range of arylboronic acid pinocol esters giving direct access to bioactive biaryls containing a benzyloxy motif under ligand-accelerated palladium catalysis. Impressively, either acetoxime can be subsequently removed without a separation, or functionalized hydroxylamine derivatives can be obtained. To gain insight into the reaction mechanism and explore the potential of exo-type acetoxime directing group in transitionmetal-catalyzed C¢H activation, further investigations are currently in progress in our lab.
Experimental Section General procedure for the palladium(II)-catalyzed acetoxime-directed ortho-arylation of aromatic alcohols (Schemes 2 and 3) To a 20 mL sealed tube (with a Teflon cap) equipped with a magnetic stir bar, the following were added sequentially: Pd(TFA)2 (6.6 mg, 0.02 mmol, 10 mol %), Ac-Gly-OH (2.3 mg, 0.02 mmol, 10 mol %), Ag2CO3 (110.3 mg, 0.4 mmol, 2.0 equiv), KBF4 (50.4 mg, 0.4 mmol, 2.0 equiv), phenylboronic acid pinacol ester 2 (0.4 mmol, 2.0 equiv), and acetoxime ether 1 (0.2 mmol, 1.0 equiv). t-AmylOH(0.5 mL) was carefully added to rinse the chemical on the inner side wall of the tube. The tube was then capped and submerged in a preheated 120 8C oil bath. The reaction was stirred for 10 h and cooled down to room temperature. The crude reaction mixture was diluted with EtOAc (6 mL) and filtered through a short pad of Celite. The sealed tube and Celite pad were washed with an additional 10 mL of EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography or preparative TLC using EtOAc/hexane 1:50 as the eluent.
Acknowledgements We gratefully acknowledge the Natural Science Foundation of Jiangsu Province of China (BK20130294), the Young National Chem. Eur. J. 2015, 21, 17474 – 17478
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Received: August 19, 2015 Published online on October 9, 2015
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& C¢H Activation
Palladium(II)-Catalyzed Acetoxime Directed ortho-Arylation of Aromatic Alcohols Kun Guo,[a] Xiaolan Chen,[a] Jingyu Zhang,[b] and Yingsheng Zhao*[a] Abstract: Biaryls, which contained a benzyloxy motif, were directly constructed through a ligand-promoted PdII-catalyzed ortho-arylation of masked aromatic alcohols. A variety of acetoxime ethers could be coupled with a diverse range of arylboronic acid pinocol esters, giving direct access to
Introduction Development of controlling site-specific functionalization of C¢H bonds offers an innovative approach to construct the core structures of pharmaceutical agents, natural products, and organic materials.[1] Harnessing a directing group to enable site-selective C¢H functionalization is one of the most successful strategies;[2] however, such transformations are sometimes in conflict with the directing groups available in a particular starting material. Despite great efforts that have been made in the last few decades to exploit varieties of auxiliaries for amines,[3] acids,[4] and ketones[5] in transition-metalcatalyzed direct C¢H functionalization, it remains a significant challenge to develop alcohol or masked alcohol-directed C¢H oxidation and C¢C formation reactions,[6] due to the possible oxidation of the hydroxyl group, weak coordination of alcohols with PdII, and the constraints of introducing suitable surrogate groups for alcohols. In 2010, breakthroughs were achieved by Yu and co-workers, who made a series of reports on PdII-catalyzed hydroxy-directed ortho-olefination,[7] intramolecular cyclization,[8] and carbonylation[9] of phenethyl alcohols. However, the use of secondaryor primary alcohols afforded lower yields. Meanwhile, Hartwig and co-workers developed a practical hydroxyl-directed orthosilylation of benzyl alcohols by employing an Ir catalyst, followed by a separate Hiyama-type coupling of the benzoxasiloles with aryl halides.[10] Despite these advances, there is still
bioactive biaryls in modest to good yield. Not only could acetoxime be subsequently removed without a separation, functionalized hydroxylamine derivatives could also be obtained.
a demand to more efficiently and directly construct biaryls containing a benzyloxy motif, which are the omnipresent component of many drug candidates, for example, in known HNF4a modulators,[11] JTT-305,[12] and VEGF receptor inhibitors[13] (Figure 1; HNF = hepatocyte nuclear factor, VEGF = vascular en-
Figure 1. Biologically active compounds containing a benzyloxy motif.
dothelial growth factor). Recently, our group reported acetoxime directed ortho-olefination of masked aromatic alcohols through a six- or seven-membered exo-palladacycle (Scheme 1 A).[14] Though the crystallization of exo-palladacycle intermediate demonstrated the ability of exo-directing mode, we have not tapped its potential. Herein, we report the first PdII-catalyzed cross-coupling of O-benzylacetoximes with arylboron reagents, in which oxime serves as an exo-type directing
[a] K. Guo, X. Chen, Prof. Dr. Y. Zhao Key Laboratory of Organic Synthesis, Jiangsu Province College of Chemistry Chemical Engineering and Materials Science, Soochow University Suzhou 215123 (P. R. China) E-mail: [email protected] [b] Dr. J. Zhang College of Physics Optoelectronics and Energy & Collaborative Innovation Center Suzhou Nano Science and Technology, Soochow University Suzhou 215006 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201503284. Chem. Eur. J. 2015, 21, 17474 – 17478
Scheme 1. PdII-catalyzed acetoxime-assisted C¢H functionalization. NHPI = Nhydroxyphthalimide, DEAD = diethyl azodicarboxylate.
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Full Paper group, and can be subsequently removed without a separation (Scheme 1 B). While oxime is well-known for transition-metal-catalyzed C¢H activation of masked ketones,[5, 15] Dong and co-workers developed the first exo-oxime-directed acetoxylation of masked alcohols under PdII/PdIV catalysis.[16] In this seminal report, they developed a catalytic alcohol b-C(sp3)¢H activation and C¢O formation reaction, where using a 2,6-dimethoxylbenzaldoxime as novel bidentate directing group was found to be crucial.[16a] Later, they expanded its application in Pd-catalyzed ortho-acetoxylation of masked benzyl alcohol.[16b] However, we envisioned that using concise acetoxime as monodentate directing group should also be beneficial to the arene C¢H activation, because 1) O-benzylacetoximes are simple and readily available, which can be easily synthesized from an SN2 reaction of benzyl halides with acetone oxime,[17] or prepared from widely available alcohols though a one-pot procedure (Scheme 1); 2) the acidic a-hydrogens in acetoxime are rather stable under mild oxidative conditions;[14] 3) tuning the reactivity and selectivity of catalysts can be achieved through the use of external ligands;[18] 4) not only is acetoxime used as a traceless directing group, but hydroxylamine[13, 19] also exists in bioactive molecules.
Table 1. Optimization of reaction conditions.[a]
Results and Discussion Initially, we treated acetoxime ether 1 a with phenylboronic acid pinacol ester 2 a at 120 8C for 10 h with a combination of different oxidants, bases, and ligands (Table 1). Preliminary results revealed that the use of Pd(TFA)2 (10 mol %), Ac-Gly-OH (10 mol %), and Ag2CO3 (2 equiv) in t-amylOH (0.5 mL) gave the ortho-arylation product 3 a in 85 % yield (Table 1, entry 1). In a further investigation into the performance of different bases, no positive effect was observed in the presence of common weak bases (entries 2–8). Interestingly, the addition of KBF4 facilitated this transformation, giving 3 a in 93 % yield (entry 9). Although the reason needs to be further explored, we speculated that the KBF4 would play the role of a pH buffer in the catalytic cycle, which would stabilize the palladium intermediate. Among the palladium catalysts screened, though Pd(OAc)2, Pd(PPh3)Cl2, Pd(CH3CN)2Cl2, and PdCl2 resulted in moderate to good yield (entries 10–13), Pd(TFA)2 was found to be superior. Because of competitive PdII-mediated protonation and homocoupling of the arylboron reagents, the use of 10 mol % of catalyst was deemed necessary (entries 9 and 14). Having identified the best catalyst, we proceeded to evaluate the optimal oxidant. The oxidants such as AgOAc, Ag2O, Cu(OAc)2, and 1,4-benzoquinone (BQ) were all tested (entries 15–18); however, Ag2CO3 still turned out to be the best. From previous studies, the ligands can adjust the steric and electronic properties of coordinated PdII centre.[18d,e,g, 20] Thus, the ligand of Ac-Gly-OH, which could significantly promote C(sp2)¢H activation and subsequent coupling reactions, was indispensable (entries 9 and 19). In the absence of a palladium catalyst, the control experiment gave no product (entry 20). With optimized conditions for the cross-coupling in hand, various masked aromatic alcohols were prepared and examChem. Eur. J. 2015, 21, 17474 – 17478
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Entry
Catalyst
Oxidant
Base
Yield[b] [%]
1 2 3 4 5 6 7 8 9 10 11 12 13 14[c] 15 16 17 18 19[e] 20
Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(OAc)2 Pd(PPh3)Cl2 Pd(CH3CN)2Cl2 PdCl2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 -
Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2O AgOAc[d] Cu(OAc)2 BQ Ag2CO3 Ag2CO3
– K3PO4 K2HPO4 KH2PO4 NaHCO3 Na2CO3 Li2CO3 NaBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4 KBF4
85 5 31 83 49 38 87 84 93 51 77 80 77 84 18 39 12 3 8 0
[a] Reaction conditions: 1 a (0.2 mmol), 2 a (0.4 mmol), Pd catalyst (10 mol %), oxidant (2.0 equiv), base (2.0 equiv) in t-amylOH (0.5 mL), 120 8C, 10 h. [b] GC yield determined using tridecane as internal standard. [c] Pd(TFA)2 (5 mol %), Ac-Gly-OH (5 mol %). [d] AgOAc (4 equiv). [e] Without Ac-Gly-OH.
ined to test the generality of this methodology (Scheme 2). To our great delight, the electron-rich arenes provided the corresponding arylated products in moderate to good yield (3 c– g, i, j). In particular, both meta- and para-substituted benzyl alcohol derivatives afforded the corresponding mono-arylated products in good yield (64 %–83 %). Trace diarylated products were also observed in the reaction system (3 e–h). It is probable that the steric hindrance and coordinated effect inhibited the further arylation reaction. Furthermore, the a-substituted benzyl alcohols were all well-tolerated, affording arylated products in good to excellent yield (3 k–m, q). In particular, the acetoxime-protected 1,4-benzenedimethanol gave the mono-arylated product 3 o in a synthetically acceptable yield. Rather disappointingly, O-phenylacetoxime would be completely decomposed into undetectable smaller molecules under PdII/Pd0 catalysis (3 p). In contrast, the acetoxime-protected phenethyl alcohol afforded the arylated product in good yield with 2.5 equiv of 2 a, which may go through a rare seven-membered exo-palladacycle intermediate.[14] The efficiency of this acetoxime-assisted C¢H transformation encouraged us to evaluate the scope of arylboronic acid pinacol esters (Ar-BPins). In general, various para- and meta-substituted Ar-BPins were tolerated in this transformation, affording the corresponding products in good to excellent yield (Scheme 3). Gratifyingly, this synthetic protocol is compatible with various functional groups, including F, Cl, Ac, CF3, SO2Me,
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Scheme 2. C(sp2)¢H cross-coupling of Ar-BPin with various functionalized acetoxime ethers. [a] Reaction was carried out with 2 a (0.5 mmol).
NO2, Me, and OMe. Moreover, the 2-naphthylboronic acid pinacol ester gave the corresponding coupling product in good yield (4 g). Unfortunately, poor conversions were obtained for ortho-substituents on account of steric hindrance (4 n and 4 o). Similarly, heteroarylboronates that contained thianaphthene (4 p) and furan (4 q) were unreactive under this condition. To further demonstrate the synthetic simplicity and versatility of the acetoxime group, we developed a sequential procedure, which could accomplish arylation and removal of the directing group with one separation, to access arylated benzyl alcohols (Scheme 4). The key to make this protocol successful depends on the reduction of acetoxime by Raney Ni catalyst.[14] Alternatively, hydrolysis of acetoxime could obtain hydroxylamine derivatives.[21] Based on the above results and pioneering studies,[3f,g,h, 5a, 16, 18d, 22] the mechanism of acetoxime-directed orthoarylation reaction is proposed as depicted in Scheme 5.To begin with, the PdII species A, which is bound by amino acid ligand, coordinates with the substrate 1 and subsequently activates the ortho-C¢H bond, forming a six-membered exo-palladacycle intermediate B.[14] Transmetalation with Ar-BPin 2 produces intermediate C,[18d, 3h] followed by reductive elimination, Chem. Eur. J. 2015, 21, 17474 – 17478
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Scheme 3. C(sp2)¢H cross-coupling of acetoxime ethers with different ArBPins. [a] Reaction was carried out with 2 (0.5 mmol).
Scheme 4. Sequential arylation and removal of directing group.
releases the target molecule 3, with concomitant generation of Pd0 species D. Reoxidation with 2 equiv of AgI regenerates the active PdII species A for another catalytic cycle.
Conclusion We have developed the first example of acetoxime-directed ortho-arylation of masked aromatic alcohol derivatives via the
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Full Paper Natural Science Foundation of China (No. 21402133), and PAPD for financial support. Keywords: alcohols · arylation · C¢H activation · crosscoupling · synthetic methods
Scheme 5. Proposed catalytic cycle.
possible six- and seven-membered exo-palladacycle intermediate. A variety of acetoxime ethers can be coupled with a diverse range of arylboronic acid pinocol esters giving direct access to bioactive biaryls containing a benzyloxy motif under ligand-accelerated palladium catalysis. Impressively, either acetoxime can be subsequently removed without a separation, or functionalized hydroxylamine derivatives can be obtained. To gain insight into the reaction mechanism and explore the potential of exo-type acetoxime directing group in transitionmetal-catalyzed C¢H activation, further investigations are currently in progress in our lab.
Experimental Section General procedure for the palladium(II)-catalyzed acetoxime-directed ortho-arylation of aromatic alcohols (Schemes 2 and 3) To a 20 mL sealed tube (with a Teflon cap) equipped with a magnetic stir bar, the following were added sequentially: Pd(TFA)2 (6.6 mg, 0.02 mmol, 10 mol %), Ac-Gly-OH (2.3 mg, 0.02 mmol, 10 mol %), Ag2CO3 (110.3 mg, 0.4 mmol, 2.0 equiv), KBF4 (50.4 mg, 0.4 mmol, 2.0 equiv), phenylboronic acid pinacol ester 2 (0.4 mmol, 2.0 equiv), and acetoxime ether 1 (0.2 mmol, 1.0 equiv). t-AmylOH(0.5 mL) was carefully added to rinse the chemical on the inner side wall of the tube. The tube was then capped and submerged in a preheated 120 8C oil bath. The reaction was stirred for 10 h and cooled down to room temperature. The crude reaction mixture was diluted with EtOAc (6 mL) and filtered through a short pad of Celite. The sealed tube and Celite pad were washed with an additional 10 mL of EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography or preparative TLC using EtOAc/hexane 1:50 as the eluent.
Acknowledgements We gratefully acknowledge the Natural Science Foundation of Jiangsu Province of China (BK20130294), the Young National Chem. Eur. J. 2015, 21, 17474 – 17478
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Received: August 19, 2015 Published online on October 9, 2015
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